Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia.

A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Aip1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiologic processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function produce a dramatic phenotype gradient. While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow-derived yet nonlymphoid in origin, is characterized by a massive infiltration of neutrophils into inflammatory lesions. Cytoskeletal responses are impaired in Wdr1 mutant neutrophils. These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types.

Phosphorylation of the proline-rich domain of Xp95 modulates Xp95 interaction with partner proteins.

The mammalian adaptor protein Alix [ALG-2 (apoptosis-linked-gene-2 product)-interacting protein X] belongs to a conserved family of proteins that have in common an N-terminal Bro1 domain and a C-terminal PRD (proline-rich domain), both of which mediate partner protein interactions. Following our previous finding that Xp95, the Xenopus orthologue of Alix, undergoes a phosphorylation-dependent gel mobility shift during progesteroneinduced oocyte meiotic maturation, we explored potential regulation of Xp95/Alix by protein phosphorylation in hormone-induced cell cycle re-entry or M-phase induction. By MALDI-TOF (matrix-assisted laser-desorption ionization-time-of-flight) MS analyses and gel mobility-shift assays, Xp95 is phosphorylated at multiple sites within the N-terminal half of the PRD during Xenopus oocyte maturation, and a similar region in Alix is phosphorylated in mitotically arrested but not serum-stimulated mammalian cells. By tandem MS, Thr745 within this region, which localizes in a conserved binding site to the adaptor protein SETA [SH3 (Src homology 3) domain-containing, expressed in tumorigenic astrocytes] CIN85 (a-cyano-4-hydroxycinnamate)/SH3KBP1 (SH3-domain kinase-binding protein 1), is one of the phosphorylation sites in Xp95. Results from GST (glutathione S-transferase)-pull down and peptide binding/competition assays further demonstrate that the Thr745 phosphorylation inhibits Xp95 interaction with the second SH3 domain of SETA. However, immunoprecipitates of Xp95 from extracts of M-phase-arrested mature oocytes contained additional partner proteins as compared with immunoprecipitates from extracts of G2-arrested immature oocytes. The deubiquitinase AMSH (associated molecule with the SH3 domain of signal transducing adaptor molecule) specifically interacts with phosphorylated Xp95 in M-phase cell lysates. These findings establish that Xp95/Alix is phosphorylated within the PRD during M-phase induction, and indicate that the phosphorylation may both positively and negatively modulate their interaction with partner proteins.

Phosphorylation of the proline-rich domain of Xp95 modulates Xp95 interaction with partner proteins.

The mammalian adaptor protein Alix [ALG-2 (apoptosis-linked-gene-2 product)-interacting protein X] belongs to a conserved family of proteins that have in common an N-terminal Bro1 domain and a C-terminal PRD (proline-rich domain), both of which mediate partner protein interactions. Following our previous finding that Xp95, the Xenopus orthologue of Alix, undergoes a phosphorylation-dependent gel mobility shift during progesteroneinduced oocyte meiotic maturation, we explored potential regulation of Xp95/Alix by protein phosphorylation in hormone-induced cell cycle re-entry or M-phase induction. By MALDI-TOF (matrix-assisted laser-desorption ionization-time-of-flight) MS analyses and gel mobility-shift assays, Xp95 is phosphorylated at multiple sites within the N-terminal half of the PRD during Xenopus oocyte maturation, and a similar region in Alix is phosphorylated in mitotically arrested but not serum-stimulated mammalian cells. By tandem MS, Thr745 within this region, which localizes in a conserved binding site to the adaptor protein SETA [SH3 (Src homology 3) domain-containing, expressed in tumorigenic astrocytes] CIN85 (a-cyano-4-hydroxycinnamate)/SH3KBP1 (SH3-domain kinase-binding protein 1), is one of the phosphorylation sites in Xp95. Results from GST (glutathione S-transferase)-pull down and peptide binding/competition assays further demonstrate that the Thr745 phosphorylation inhibits Xp95 interaction with the second SH3 domain of SETA. However, immunoprecipitates of Xp95 from extracts of M-phase-arrested mature oocytes contained additional partner proteins as compared with immunoprecipitates from extracts of G2-arrested immature oocytes. The deubiquitinase AMSH (associated molecule with the SH3 domain of signal transducing adaptor molecule) specifically interacts with phosphorylated Xp95 in M-phase cell lysates. These findings establish that Xp95/Alix is phosphorylated within the PRD during M-phase induction, and indicate that the phosphorylation may both positively and negatively modulate their interaction with partner proteins.

The effect of African Americans' ethnographic paradigms and cultural explanatory model of breast cancer in framing the male partner's attitudes and behaviors about the woman's breast cancer diagnosis

The disparate burden of breast cancer-related morbidity and mortality experienced by African American women compared with women of other races is a topic of intense debate in the medical and public health arenas. The anomaly is consistently attributed to the fact that at diagnosis, a large proportion of African American women have advanced-stage disease. Extensive research has documented the impacts of cultural factors and of socioeconomic factors in shaping African American women's breast-health practices; however, there is another factor of a more subtle influence that might have some role in establishing these women's vulnerability to this disease: the lack of or perceived lack of partner support. Themes expressed in the research literature reflect that many African American breast cancer patients and survivors consider their male partners as being apathetic and nonsupportive. ^ The purpose of this study was to learn how African American couples' ethnographic paradigms and cultural explanatory model of breast cancer frame the male partners' responses to the women's diagnosis and to assess his ability to cope and willingness to adapt to the subsequent challenges. The goal of the study was to determine whether these men's coping and adaptation skills positively or negatively affect the women's self-care attitudes and behaviors. ^ This study involved 4 African American couples in which the woman was a breast cancer survivor. Participants were recruited through a community-based cancer support group and a church-based cancer support group. Recruitment sessions were held at regular meetings of these organizations. Accrual took 2 months. In separate sessions, each male partner and each survivor completed a demographic survey and a questionnaire and were interviewed. Additionally, the couples were asked to participate in a communications activity (Adinkra). This activity was not done to fulfill any part of the study purpose and was not included in the data analysis; rather, it was done to assess its potential use as an intervention to promote dialogue between African American partners about the experience of breast cancer. ^ The questionnaire was analyzed on the basis of a coding schema and the interview responses were analyzed on the principles of hermeneutic phenomenology. In both cases, the instruments were used to determine whether the partner's coping skills reflected a compassionate attitude (positive response) versus an apathetic attitude (negative response) and whether his adaptation skills reflected supportive behaviors (the positive response) versus nonsupportive behaviors (the negative response). Overall, the women's responses showed that they perceived of their partners as being compassionate, yet nonsupportive, and the partner's perceived of themselves likewise. Only half of the women said that their partners' coping and adaptation abilities enabled them to relinquish traditional concepts of control and focus on their own well-being. ^ The themes that emerged indicate that African American men's attitudes and behaviors regarding his female partner's diagnosis of breast cancer and his ability to cope and willingness to adapt are influenced by their ritualistic mantras, folk beliefs, religious teachings/spiritual values, existential ideologies, socioeconomic status, and environmental factors and by their established perceptions of what causes breast cancer, what the treatments and outcomes are, and how the disease affects the entire family, particularly him. These findings imply that a culturally specific intervention might be useful in educating African American men about breast cancer and their roles in supporting their female partners, physically and psychologically, during diagnosis, treatment, and recovery. ^

Qualitative study: Understanding Mexican American women's experience in intimate partner violence

The purpose of this qualitative study was to gain an understanding of the experiences of Mexican American women living with intimate partner abuse relevant to the process of disclosure of abuse. Limited research exists on the experiences of women who are of Mexican descent living with intimate partner abuse and their disclosure of abuse. Factors that influence disclosure for other populations are well articulated in the literature however, these factors have not been adequately verified in persons of Mexican descent. Data are reported from in-depth interviews with 26 clients at a shelter and an outreach agency in a south Texas-Mexico border community. Semi-structured interview guide was used to elicit information over an 11 month period. A grounded theory ethnography approach was used to analyze data. Verification strategies and constant comparison techniques (e.g. investigator responsiveness, methodological coherence, sampling adequacy, an active analytic stance, and saturation) enhanced rigor of analysis. Nineteen Mexican immigrant women and seven Mexican American women participated in the study. Several themes were discerned related to women's experiences in abuse: painful living, questioning endurance, and confronting reality. In almost every participant's account there was a description of repeated victimization by her intimate partner or partners, and again, by others within and outside her network. The participants discussed several cultural factors (e.g. embarrassment, concerns for family, avoidance of causing pain to family, protection of partner, avoidance of being judged) that hindered their decisions whether or not to disclose. Participants noted that healthcare workers rarely asked probing questions regarding abuse. The timing and process of disclosure took many turns for women in this study. Some of the factors hindering women from disclosing were found to be influenced by cultural practices. The consequences of disclosure for many of the women led them to re-victimization. Implications for practice to avoid missed opportunities with women living in abuse are to: ask questions routinely to encourage disclosure of abuse and offer community resource information for women living in abuse or both.^

A global perspective on intimate partner violence during pregnancy: An analysis of twelve developing countries

Violence against women has been recognized as a significant worldwide human rights issue and public health problem. Women of reproductive age may be particularly at risk, and pregnancy may trigger or escalate violence. Using data available from Demographic and Health Surveys on 271,103 women of reproductive age (15-49) from Bolivia, Cameroon, Colombia, Dominican Republic, Egypt, Haiti, India, Kenya, Nicaragua, Peru, South Africa, and Zambia, this study examined the nature of domestic violence during pregnancy in developing countries, including prevalence, demographic and risk factors, maternal and child health outcomes, perpetrators of violence, help-seeking behavior, and social support. In the majority of countries analyzed, violence during pregnancy consistently occurred at approximately one-third the rate at which domestic violence occurred overall. Younger women and women with more children were particularly at risk. Abuse during pregnancy was significantly associated with history of a terminated pregnancy and under-5 child mortality in most countries, and with neonatal and post-neonatal mortality in most Latin American countries. Women who were abused during pregnancy were most often abused by their current or former husband or boyfriend and most never attempted to seek help. In most countries that examined social support, women abused during pregnancy had significantly less contact with family and friends. Implications for practice and research are discussed. ^

Pregnancy intention, intimate partner violence, and the use of prenatal care in Jordan

Previous research has suggested an association between intimate partner violence and pregnancy intention status, and pregnancy intention status and the use of prenatal care services, however much of these studies have been conducted in high income countries (HIC) rather than low and middle income countries (LMIC). The objectives of this study were to examine the relationship between pregnancy intention status and intimate partner violence, and pregnancy intention status and the use of prenatal care among ever-married women in Jordan.^ Data were collected from a nationally representative sample of women interviewed in the 2007 Jordan Demographic and Health Survey. The sample was restricted to ever-married women, 15–49 years of age, who had a live birth within the five years preceding the survey. Multivariate logistic regression analyses was used to determine the relationship between intimate partner violence and pregnancy intention status, and pregnancy intention status and the use of prenatal care services.^ Women who reported a mistimed pregnancy (PORadj 1.96, 95% CI: 1.31–2.95), as well as an unwanted pregnancy (PORadj 1.32, 95% CI: 0.80–2.18) had a higher odds of experiencing lifetime physical and/or sexual abuse compared with women reporting a wanted pregnancy. Women not initiating prenatal care by the end of the first trimester had statistically significant higher odds of reporting both a mistimed (PORadj 2.07, 95% CI: 1.55–2.77) and unwanted pregnancy (PORadj 2.36, 95% CI: 1.68–3.31), compared with women initiating care in the first trimester. Additionally, women not receiving the adequate number of prenatal care visits for their last pregnancy had a higher odds of reporting an unwanted pregnancy (PORadj 2.11, 95% CI: 1.35–3.29) and mistimed pregnancy (POR adj 1.41, 95% CI: 0.96–2.07).^ Reducing intimate partner violence may decrease the prevalence of mistimed or unwanted pregnancies, and reducing both unwanted and mistimed pregnancies may decrease the prevalence of women not receiving timely and adequate prenatal care among women in this population. Further research, particularly in LMIC, is needed regarding the determinants of unintended pregnancy and its association with intimate partner violence as well as with the use of prenatal care services. ^

Exploring the Benefits of a Parent Partner Mentoring Program in Child Welfare

Parent partner mentoring programs are an innovative strategy for child welfare agencies to engage families in case planning and service delivery. These programs recruit and train parents who have been involved in the system and have successfully resolved identified child abuse or neglect issues to work with families with current open cases in the child welfare system. Parent partner mentors can provide social and emotional support, advocacy, and practical advice for navigating this challenging system. Insofar as parent partners share similar experiences, and cultural and socioeconomic characteristics of families, they may be more successful in engaging families and building trusting supportive relationships. The current study presents qualitative data from interviews and case studies of families who were matched with a parent partner in a large county in a Midwestern state. Interviews with families, parent partner mentors, child welfare agency staff, and community partners and providers suggest that parent partner programs may be just as beneficial for parent partner mentors as they are for families being mentored. These programs can build professional skills, help improve self-esteem, provide an avenue for social support, and may potentially prevent recidivism. Parent Partner programs also provide a mechanism for amplifying family voice at all levels of the agency.